SIGNA VITAE 2006; 1(1): 9 - 12

REVIEW

Vasoactive Agents
INO HUSEDZINOVIĆ • NIKOLA BRADIĆ • TANJA GORANOVIĆ

INO HUSEDINOVIĆ (  ) •
NIKOLA BRADIĆ • TANJA GORANOVIĆ
Department for anesthesiology,
reanimatology and intensive care medicine
University Hospital Dubrava
Gojko Šušak Avenue No 6
10000 Zagreb, Croatia
Phone: +385 1 290 3197
Fax: +385 1 290 3440
e-mail: inoh@kbd.hr

ABSTRACT
This article is a short review of vasoactive drugs which are in use in todays clinical practice. In the past century, development
of vasoactive drugs went through several phases. All of these drugs are today divided into several groups, depending on their
place of action, pharmacological pathways and/or effects on target organ or organ system. Hence, many different agents are
today in clinical practice, we have shown comparison between them. These agents provide new directions in the treatment of
cardiovascular compromise, suggesting that the primary goal of therapy is to produce a vasodilatory effect of the circulation
rather than to reverse hemodynamic failure by using inotropic agents, with their inherent risks and side effects.

Key words: vasoactive agents, inotropic agents, levosimendan, phosphodiesterase III inhibitors
Vasoactive agents are a group of bioactive chemicals, which change vasomotor
tone through their influence on various
peripheral receptors. Most of these agents have inotropic effects (e.g. norepinephrine) as they bind with receptors positioned on the surface of the myocardium.
Some pharmacologic agents are difficult
to classify as their effects overlap, however all vasoactive drugs affect stroke
volume and heart rate. This determines
cardiac output and, as a consequence,
overall cardiovascular function.
In the ideal situation, inotropic drugs
would only have effects directly on myocardial cells, without simultaneous stimulation of other receptors. As one quickly
learns, such is not the case with many of
our most important vasoactive agents.
Some inotropic agents such as dopamine
(depending on the dose) provoke vasoconstriction while other such agents, like
isoprenaline, cause vasodilatation.
Pure vasoconstrictors produce arterial
wall constriction by stimulation of α-adrenergic receptors (e.g. phenylephrine) or by
stimulating V1a receptors (e.g. vasopresine) on the vascular endothelial surfaces.
Pure vasodilators, on the other hand, are
classified according to their predominate
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effect on the arteries (e.g. hydralazine),
veins (e.g. nitroglycerine), or both arterial
and venous (e.g. nitropruside) vessels.
The main favorable result of hydralazine
and nitropruside is a reduction of cardiac afterload and an increase in cardiac
output. The main effect of nitroglycerine is achieved by venodilatation, which
Table 1. cAMP dependent inotropic
agents

INOTROPIC AGENTS
cAMP dependent
adrenergic agonists
epinephrine
isoproterenol
dobutamine
norepinephrine
xamoterol
dopaminergic agonists
dopamine
dopexamine
ibopamine
phosphodiesterase III isoenzime inhibitors
derivate of biperidine - amrinone, milrinone
derivate of imidazolone - enoximone,
piroximone
toborinone

decreases preload and consequently
cardiac output.
In 1908, Sir James McKenzie first described “low cardiac output syndrome”.
Clinically, this syndrome results in global
hypoperfusion, whose treatment requires inotropic support by vasoactive
medications, or mechanical intervention
to support and improve cardiac work. In
the early 1900s′ the mainstay of cardiac
treatment was digitalis with the addition
of a salt reduced diet. Accumulated fluids within pleural and peritoneal spaces
were eliminated by mechanical means
or by drainage. The use of diuretics was
instituted during the 1920’s. The treatment
of congestive heart failure entered a second phase in the 1950’s, when vasodilators were introduced into the physicians’
therapeutic armamentarium. With the
introduction of the inotropic agents in the
1980s’, a third great period in the therapy
of heart failure had begun.
Using the pharmacokinetics and pharmacodynamics of many inotropic agents,
Lehtonen was able to categorize them
into two basic groups: cAMP dependent (Table 1), and cAMP independent
(Table 2) (1).
The cAMP dependent group consists of
those agents, which increase production of cAMP by stimulating adrenergic
receptors (adrenergic and dopaminer9

Table 2. cAMP independent inotropic
agents

INOTROPIC AGENTS
cAMP independent
Na+-K+-ATPase inhibitors
digoxin
potassium channels inhibitors
vesnarinone
agonists of β- adrenergic receptors
phenylephrine
Calcium
gic agonists) or by decreasing cAMP
degradation by inhibiting phosphodiesterase activity (phosphodiesterase
III inhibitors). In contrast, the groups of
inotropic agents, which are in the cAMP
independent group, are inhibitors of
Na+-K+-ATPase (digoxin), potassium
channel inhibitors (vesnarinon), agonists of ß- adrenergic receptors (phenylephrine), and include the calcium
salts. The agents in this latter group
affect ionic pumps and regulate the
concentration of intracellular calcium
(Table 3).
The catecholamine inotropic agents
were among the earliest vasoactive
agents and remain important and useful
today although there can be some negative consequences of their use (Table
4). A major side effect is an increase
Table 3. Older therapeutic medications

OLDER THERAPEUTIC

in myocardial oxygen consumption.
Furthermore, it is well established that
during dopamine administration its
effectiveness diminishes significantly
as administration continues beyond 48
hours. This same effect has been seen
after 90 hours with dobutamine. The
most important component to explain
Table 4. Adverse effects of catecholamine administration

ADVERSE EFFECTS OF CATECHOLAMINE ADMINISTRATION
increase in oxygen consumption
arrhythmogenic effect
tachyphylaxis
increased risk of sudden cardiac death
difficulty during β-blocker administration
Dependency on the functional condition of ß-adrenergic receptors
the decreased effectiveness of inotropic agents is the functional condition
of the β-adrenergic receptors. Today,
there are many known conditions which
change the density and responsiveness of β-adrenergic receptors. Such
conditions, in fact, change the relationship within subgroups of β-adrenergic

receptors in myocardium, from 80%
β1: 20% β2 changing in 60% β1: 40%
β2 (Table 5) (2).
Phosphodiesterase III inhibitors produce their effects independently of βadrenergic receptors. They are a useful
class of agents that can be employed
in various therapeutic settings. They are
a non-specific heterogeneous group of
agents. All three phosphodiesterase
fractions are physiologically active.
They have strong chronotropic effects,
and therefore should be avoided in
clinical practice when an inotropic
agent is needed. Specific inhibitors of
this class of agents are divided into the
two groups (Table 6) (2).
There is also a group of vasoactive agents that exhibit an inotropic effect, but in
addition, also have a vasodilator effect.
Opie grouped these agents into a unique
class, the inodilators (Table 7) (3).
A lack of tachyphylaxis and tachycardia, and being independent of βadrenergic receptor conditions, gives
a clinical advantage to this group of
agents, when comparing them with the
catecholamines (Table 8).
Furthermore, these agents have a very
important myocardial effect, called the

Table 5. Conditions that alter receptor density and affect response to catecholamines
Legend: *ß -adrenergic receptors are decreased in severe heart failure; + if on

ß - agonists therapy for asthma; ↑ - increased; ↓ - decreased. Modified from:
Zaritsky A, Eisenberg MG. Ontogenetic consideration in the pharmacotherapy
of shock. In: Chernow B, Shoemarker WC, eds. Critical Care: State of the Art.
Fullerton, CA: Society of Critical Care Medicine; 1986;7:485-534

MEDICATIONS

CONDITIONS THAT ALTER RECEPTOR DENSITY AND AFFECT RESPONSE

NOTE: treatment of acute heart failure

TO CATECHOLAMINES

did not change for decades

CONDITION

RECEPTOR DENSITY CHANGE

morphine

congestive heart failure

↑ β (heart)*

diuretics

sepsis

↓ α (liver, vasculature)

nitroglycerine

myocardial ischemia

↓ β, ?? (heart)

catecholamine inotropic agents

asthma

↓ β (lungs leukocytes)+

Despite acute hemodynamic improve-

cystic fibrosis

↓ β (leukocytes)

ment, inotropic agents often increased

agonist administration

↓ α, β (heart, platelets, leukocytes)

mortality

antagonists administration

↑ α, β (heart, platelets, leukocytes)

epinephrine

hyperthyroidism

↑ β (heart)

dobutamine

hypothyroidism

↓ β (heart)

milrinone

glucocorticoids

↑ β (heart, leukocytes)

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Table 6. Phosphodiesterase iii
inhibitors

Table 8. Advantages of phosphodiesterase III inhibitors

PHOSPHODIESTERASE III INHIBI-

ADVANTAGES OF PHOSPHODIE-

TORS (PDE III)

STERASE III INHIBITORS

NON-SPECIFIC

myocardial - positive lusitropic effect

theophyline

independent of the functional condition

papaverine

of adrenergic receptors

dipyridamole

lack of tachyphylaxis

SPECIFIC

lack of tachycardia

derivates of biperidine - amrinone,
milrinone
derivates of imidazolone - enoximone,
piroximone
lusitropic effect, which was introduced
into clinical terminology by Smith and
Katz in 1986. Coining this term, the
authors wanted to emphasize the role
of diastolic dysfunction (4) during

One of the newest groups of inotropic
agents (Table 10) is a group of agents,
which increase the affinity of myofibrils
for calcium and are called calcium sensitizers. Calcium sensitizers are the newest heterogeneous group of inotropic
agents. The best known representatives of this group are levosimendan
and pimobendan. Positive inotropic

Table 7. Effects of phosphodiesterase III inhibitors

Table 10. Newer inotropic agents

NEWER INOTROPIC AGENTS
CALCIUM SENSITIZERS
levosimendan
pimobendan
OTHERS
natriuretic brain peptide - nesiritide
tezosentan
vasopressin

EFFECTS OF PHOSPHODIESTERASE III INHIBITORS
MYOCARDIUM

positive inotropic

VASCULATURE

vasodilatation

CORONARY ARTERIES

vasodilatation

PLATELETS AND LEUKOCYTES

metabolic effect

heart failure. All agents, which improve
diastolic function, primarily by decreasing the actin-myosin overlap during
diastole, are deemed to have a positive
lusitropic effect.
Numerous adverse effects and an increased mortality are the reasons why
many clinicians are often unsuccessful with the inotropic agents presently
in use. New therapeutic agents have
been developed in the last few years to
assist the clinician in the stabilization,
support and treatment of cardiovascular disease (Table 9).

inotropic agent (5). Additionally, the incidence of arrhythmias is extremely low,
there is no development of tolerance
to its pharmacological effects, and the
simultaneous administration of β-blockers and calcium channels blockers does
not produce serious adverse effects.
In two large randomized studies, RUSSLAN and LIDO, it was documented
that positive hemodynamic effects
and a lower mortality was seen in
patients who received levosimendan

effects of levosimendan are achieved
by its binding to troponin C and calcium,
thereby stabilizing the tropomyosin molecule and prolonging the duration of
actin-myosin overlap without a change
in the net concentration of intracellular calcium. The vasodilatory effect of
levosimendan is reached through activation of ATP-dependent potassium
channels. This leads to a decrease in
both afterload and preload, increased
coronary blood flow and a resultant antiischemic effect. Levosimendan is therefore categorized as an anti-ischemic

in comparison to patients who received
dobutamine or placebo (6, 7). Also,
there is much interest in levosimendan
administration in patients with openheart surgery, especially in those with
off-pump procedure (8-10).
There are three types of natriuretic brain
peptides. The A and B types are located
in the atria and ventricles of the heart,
and the C type is located in endothelial
cells. B-natriuretic peptide has a spectrum of physiologic effects of clinical
importance, which include reduction of
both pre- and afterload along with diuretic and natriuretic effects (Table 11).
The serum level of B-natriuretic peptide
is directly correlated with the degree of
chronic heart failure. Because of this, it
has been added to the diagnostic pro-

Table 9. New therapeutic goals

NEW THERAPEUTIC GOALS
AGENT

EFFECT

MECHANISM OF ACTION

ISDN - high doses

venous and arterial vasodilatation

synthesis of NO

Tezosentan

arterial vasodilatation

blockade of endothelin receptors

Nesiritide

arterial vasodilatation

decrease of preload, afterload, diuresis

Levosimendan

inotropic, vasodilatation

binding for troponin C, activation of
potassium channels

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tocol of the European Cardiology Association and to the protocol of congestive
heart failure treatment as well (11).
Nesiritide is an exogenous recombinant
B-natriuretic peptide with the same
pharmacological profile. There have
been nine clinical studies conducted
using nesiritide involving over nine hundred patients. Significant, positive clinical effects have been documented.
Endothelin is a strong vasoconstrictor. There are two types of receptors to
which it attaches. The ETa receptors are
located in the vessel’s smooth muscles
cells and the ETb receptors are located
on the endothelial surfaces. Stimulation
of the receptors by endothelin produces
increased vascular tonus and progression of arteriosclerosis in subjects with
coronary artery disease. Inhibition of
endothelin function results in better
hemodynamics, heart remodeling and a
decreased proliferation of smooth muscles in blood vessel walls. In the RITZ

study, and the VERITAS study, involving almost 1500 patients (13), favorable
hemodynamic effects (a lowering the
systemic blood pressure, and increase
of cardiac index) were measured but
without significant clinical improvement
and or a reduction in mortality (4, 5, 12).
Arginin-vasopresine is an endogenous
nonapeptide. It stimulates V1a receptors and produces vasoconstriction. At
the same time stimulation of V2 receptors produces an antidiuretic effect. By
these mechanisms vasopresine plays
an important role in fluid homeostasis.
It plays an important therapeutic role
in states of refractory vasodilatation, in
which patients are unresponsive to catecholamine vasoconstrictive therapy
(14). Vasopresine has also a place in
cardiopulmonary resuscitation procedures (15). In the animal model, it has
shown better effects on circulation in
the splanchnic region in comparison
with norepinephrine (16).

CONCLUSION
Historically, the catecholamines inotropic agents were first line medications
used in the treatment of cardiovascular
compromise, but their benefits were
often overshadowed by major complications, such as increased mortality.
The introduction of many newer agents
in newer classes, such as those which
produce their effects independently of
β-receptor functionality (e.g. phosphodiesterase III inhibitors), or do not change
the intracellular calcium values (e.g.
calcium sensitizers), represent safer,
better choices for treatment. They also
establish new directions in the treatment
of cardiovascular compromise, suggesting that the primary goal of therapy
is to produce a vasodilatory effect of
the circulation rather than to reverse
hemodynamic failure using inotropic
agents, with their inherent risks and side
effects.

LITERATURE
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4. Smith VE, Katz AM. Inotropic and lusitropic abnormalities as the basis for heart failure. Heart Failure 1987;3:55-65.
5. Lehtonen LA. Levosimendan: a parenteral calcium-sensitizing drug with additional vasodilatatory properties. Expert Opin Investing Drugs
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